The two sections of this chapter provide complementary expositions of our complex, and as yet incomplete, understanding of the biology of depression. In the first section, Adrian Dunn offers a brief historical overview of antidepressant treatments to introduce the need for conducting more extensive animal-based pharmacological validation studies of new antidepressant drugs. He describes with vivid clarity the most important behavioral tests available today to measure depressive-like symptoms in animals, such as the forced-swim test, tail-suspension test, and sucrose preference test. In addition, he discusses important biological processes that are potential markers or inducers of depression, such as the enhanced metabolism of brain tryptophan and serotonin, the inhibition of nerve regeneration in the hippocampus, and the sickness behavior induced by tumor burden and inflammatory cytokines. In the second section, Robert Dantzer and Keith Kelley offer a detailed account of the possible neuroimmune mechanisms of sickness and depression that are induced by inflammatory cytokines. They begin by describing some of the cellular changes in the brain that follow infection and inflammation in the periphery, with particular emphasis on the role of interleukin (IL)-1 and lipopolysaccharide (LPS) in the induction of neuroimmune pathways of communication. Motivational changes triggered by sensory pathways and their involvement in sickness and depression are discussed, along with the difficult task of discriminating between the two phenotypes. A detailed description is given of the possible role of indoleamine 2,3 dioxygenase (IDO) and tryptophan metabolism as one of the key molecular mechanisms that may link inflammation with depression.

Cognitive dysfunction is increasingly recognized by practitioners and researchers as one of the symptoms that cause great distress for patients with cancer, their families, and their health care providers. The prevalence of cognitive impairment varies and is based on several factors, including the amount of time the patient has had cancer, the type of cancer, the length of treatment, and the treatment used, and is estimated to affect anywhere between 17% and 75% of patients with cancer. In a series of experiments, Wefel et al. noted signs of cognitive impairment in 33% to 35% of cancer patients prior to treatment with chemotherapy and in approximately 61% of patients after chemotherapeutic treatment.

Findings such as these, coupled with the fact that treatment for cancer begins soon after diagnosis, has led to the characterization of chemotherapy-related cognitive impairments as “chemofog” or “chemobrain.” Although the nature of the impairment seems to vary among patients, those who experience chemobrain generally report subtle changes in the ability to maintain focus and engage in routine daily activities. Some investigations performed before and after the initiation of chemotherapeutic treatment find that memory, motor dexterity, and executive function (frontal subcortical components) tend to be impaired, with attention and psychomotor speed remaining unimpaired. Other studies have shown that working memory, or the ability to process information and do multiple tasks, is often impaired, whereas hippocampal components of memory, such as retention and consolidation, frequently are not.

Both cancer and cancer treatment produce multiple, disabling symptoms, the most prominent and distressing of which are addressed in this book. Our aim in assembling this volume has been to balance information from clinical research in cancer-related symptoms, including pain, fatigue, appetite and weight loss, sleep disturbance, cognitive impairment, and cancer-related affective changes, with basic laboratory research that explores, often in animal models, the potential mechanisms responsible for these symptoms.

Several chapters have considered new approaches to studying symptoms, including developing more-pertinent animal models and approaching symptoms from molecular, genetic, and neuroimaging perspectives. Other chapters have focused on issues of symptom assessment by self-report, longitudinal modeling of the relationship between symptom report and biology, and novel clinical trial designs. Finally, several chapters have addressed such real-world issues as obtaining funding for symptom research, establishing the cost-benefit of symptom management, integrating symptom research into collaborative cancer research groups, understanding regulatory guidelines for stating that symptom-relieving drugs really are effective, and exploring pathways for the development of new symptom-management agents. Together, these chapters lend support to the real possibility of a multidisciplinary collaboration that could become a science of symptoms – at least, of symptoms related to cancer.

The overarching goals of the science of symptom research are to prevent the development of symptoms and to establish new or enhanced treatment methods for the symptoms of cancer and cancer treatment, which may in turn lead to improvement in patient function, stress level, satisfaction with and willingness to endure therapy, and quality of life both during and after cancer treatment. To design treatments for the symptoms experienced by patients with cancer, it would be extremely useful to know the underlying mechanisms of those symptoms. In many areas of medicine, animal models have proven useful for suggesting underlying mechanisms of diseases and for testing appropriate therapies.

In this chapter we briefly discuss the theories underlying the use of animal models in cancer symptom research.Chapter 3 builds on this foundation with a review of animal research that may be appropriate for modeling the symptoms associated with cancer and its treatment.

The rationale for animal models

Using animal models in research

In principle, animal models can be used to mimic certain disease states, to identify potential underlying mechanisms and to test potential therapies – pharmacological, surgical, or otherwise. Th e primary rationale for using animal models is that certain exp erimental procedures are diffi cult to perform or would be considered unethical to perform in humans.

Unfortunately, pain comes in many sizes and shapes for the patient with cancer. Not only is pain caused by tissue destruction or transformation produced by the cancer itself, but it also may be a long lasting or even late effect of cancer treatment. Cancer can destroy bone and other tissue, can distort viscera, and can impinge on neural structures, all with the potential for causing pain. Cancer therapies can also result in painful neuropathy, produced by toxic or traumatic damage to peripheral and central neural structures. The two sections of this chapter report on the status of research in two common types of pain that patients with cancer may experience.

In the first section, Juan Miguel Jimenez-Andrade and Patrick Mantyh address the issue of disease-related pain, focusing primarily on pain that is the result of changes in bone produced by the cancer itself. In the second section, Haijun Zhang and Patrick Dougherty focus on pain produced as a side effect of neural destruction. Whereas pain from either source can be extremely disabling, the mechanisms causing these two types of pain are distinct, and call for differences in approaches to treatment as well as in research for developing new target agents for pain management.

More than 11 million people in the United States have a history of cancer, and more than 1.4 million new cases of the disease are diagnosed every year. Due to progress in the prevention and treatment of cancer, approximately 68% of patients now survive for at least 5 years after diagnosis; nonetheless, 18% will die, often after months of painful, progressive illness.

The symptoms experienced by patients with cancer and even cancer survivors are well known to cause significant distress, affect the ability to function, and impair rehabilitation. Whereas many of these symptoms are the result of disease, it is increasingly recognized that pain, neuropathy, fatigue, sleep disturbance, cognitive dysfunction, and affective symptoms can also be caused by the treatments for the cancer. Treatment-related symptoms may persist for weeks, months, or years and may worsen, even when the cancer improves; they can limit vocational activity and inhibit social recovery.

In many cases, cancer can be managed much like other serious chronic diseases – thus extending for many years the need for continued treatment accompanied by the frequent monitoring and managing of treatment-related symptoms. And, as patients survive cancer for increasingly longer periods, persistent residual treatment-related symptoms are becoming more prevalent and pose an increasing barrier to the resumption of predisease functioning. Treatment-related symptoms can directly affect survival if they become so severe that patients abandon potentially curative therapies. Having the ability to control or even prevent such symptoms would be of potential benefit to thousands of cancer patients and survivors.

For many patients with cancer, becoming depressed is frequently associated with both the cancer and its treatments. In a recent state-of-the-science conference, depression was highlighted as one of the most important symptoms facing patients with cancer, along with fatigue and pain. Only a small proportion of patients with cancer present with major depression as defined by the revised fourth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IVR), but depression-like symptoms, including reduced interest in previously pleasurable activities, lack of motivation, and sadness are frequently reported by patients with cancer in various stages of the disease.

It is easy to attribute these changes in affect to the patient learning that they have a potentially fatal disease. However, the degree of disturbance reported by patients is typically only modestly correlated with the severity of their disease or their prognosis. Only recently has there been interest in the association between the biological insults caused by cancer and its treatment, and the changes in affect and the other symptoms that patients report. Having a greater understanding of the biology contributing to cancer-related changes in affect should lead to better control or prevention of this source of distress.

Animal models of depressed affect related to disease burden or treatment toxicities may be important for developing a mechanistic understanding of why these changes occur. Currently, animal models of depressed affect related to cancer are relatively unexplored (but see below).